A solid pharmaceutical product, such as a tablet or capsule, is generally composed of a mixture of active ingredient(s) and excipient (i.e., pharmacologically inactive ingredients) compressed into a desired shape. When the product is administered to a patient, it is expected that the active ingredient will be released into the gastrointestinal (GI) tract in a predictable and reproducible manner. There are a number of factors which can alter the drug release characteristics of a product, and consequently the outcome in a patient. These factors include, but are not necessarily limited to: the nature and composition of active and inactive ingredients; the manufacturing process; and/or storage conditions. Federal regulations in many countries require pharmaceutical companies to determine the drug release characteristics of any new pharmaceutical product.
The methodology used to assess the drug release characteristics of a pharmaceutical product in humans is known as a bio-availability and/or bio-equivalence study, also commonly termed as a “bio-study”. A bio-availability study follows a predetermined protocol, in which a pharmaceutical product is administered to a human volunteer, and a number of blood samples are withdrawn at different time intervals. These blood samples are then analyzed to determine the level of active ingredient in the volunteer's blood. The resulting blood concentration vs. time profiles are used to assess the bio-availability and bio-equivalence of the pharmaceutical product. The profiles are also used to establish the extent and rate of drug release and absorption, and can be compared to corresponding profiles obtained from different products. This is the fundamental concept in the drug release evaluation to establish safety, efficacy and quality aspects of a drug product. Any time that a new product is developed; significant changes are made to an existing product; or the manufacturing process is altered, the drug release characteristics of the products must be re-established.
As may be appreciated, in-vivo bio-studies of the type described above tend to be expensive and time consuming. Furthermore, ethical concerns can severely limit the desirability of these studies in humans. Consequently, an in-vitro drug release evaluation test is desirable as a low-cost/low-risk alternative. Various protocols have been developed for conducting such in-vitro dissolution tests, and are routinely used for both product development and quality assurance.
Presently, drug dissolution testing is conducted using recommended compendial methods and apparatus, such as the U.S. Pharmacopoeia. Four different types of apparatus, based on different mixing methods are commonly available commercially and have compendial recognition. These apparatuses are known as: paddle; basket; flow-through; and reciprocating cylinder.
Of the four types of apparatus, the paddle apparatus is the most commonly used. Several standard paddle-type drug dissolution testing apparatus are known, such as those manufactured by Varian Inc., Distek Inc. and others. As may be seen in FIG. 1, such testing apparatus 2 typically provide between 6 and 12 substantially identical vessels 4 (only one is shown in FIG. 1), so that multiple parallel dissolution tests may be conducted simultaneously. A drive unit 6 provides a spindle 8 designed to support a respective T-shaped paddle 10 within each vessel 4, and a drive motor (not shown) for rotating each spindle 8 at a desired speed of between about 50 and 100 rpm.
While exact protocols and apparatus vary, all drug dissolution test methods involve placing the pharmaceutical product into an aqueous dissolution medium (e.g. water and/or buffers), and applying some form of agitation to the dissolution medium in order to promote disintegration and dissolution of the product under test. In the case of the paddle-type of apparatus of FIG. 1, the pharmaceutical product is placed into an aqueous dissolution medium 12 within a vessel 4, and agitation to the dissolution medium is achieved by rotating a paddle 10 at a speed of between 50 and 100 rpm. At specific times, samples of the dissolution medium 12 are withdrawn and the percentage of dissolved active ingredient determined using any of the conventional analytical methods, such as UV or liquid chromatography. Cumulative drug release as a percentage of the dosage strength is then calculated and reported, describing the drug release characteristic in vitro. The concentration vs. time profiles can be used to gauge of the rate of dissolution of the pharmaceutical product. The logic behind assessing the drug release in water or aqueous buffer solution is that, if a drug is to be absorbed from the GI tract into the systemic circulation, the drug has to be in a solution form. Thus, knowledge of the drug dissolution rate should, at least in theory, be usable as a proxy for the bio-availability.
In principle, drug dissolution testing should provide an alternative to bio-availability studies in humans that is fast, safe and low cost. However, all of the prior art dissolution testing methods suffer a limitation in that they are fundamentally non-reproducible. Successive tests with samples of the same pharmaceutical product (even within the same production lot), and using the same type of test apparatus and protocol, can yield widely differing results. The disparity can be mitigated, to some degree, by use of automation to eliminate human factors influencing the test protocol, and by averaging results over a very large number of product samples. However, even with these measures, the standard deviation of the test results can still be so wide as to prevent statistically valid comparison between different pharmaceutical products, or even between different production lots of the same product. In some cases, successive tests using identically the same test apparatus will produce self-consistent (and thus repeatable) test results. However, these results will generally not correlate well with test results produced by another test apparatus, even when the two devices are manufactured to identical specifications, by the same company.
Furthermore, it would be highly desirable for drug dissolution test results of a product to at least roughly correlate to those of the bio-studies of the same product. For example, it would be desirable for the concentration vs. time profile produced by the drug dissolution test to at least roughly correlate with the corresponding concentration vs. time profile produced by the corresponding bio-availability study. Such correlation would enable the rate of dissolution found during a dissolution test to be used as an indicator of the dissolution rate in the GI tract. However, in most cases, dissolution test results cannot be correlated with bio-studies of the same product in any statistically valid manner.
The source of non-repeatability and non-reproducibility in conventional drug dissolution testing apparatus depends of the type of apparatus used. In the case of the paddle apparatus shown in FIG. 1, a major source of error lies in the fact that the paddle 10 efficiently transfers rotary motion to the surrounding dissolution medium 12. Consequently, during a dissolution test, the paddle 10 induces bulk rotation of the dissolution medium 12 within the vessel 4 (as shown by dashed arrows in FIG. 1). Over time, the bulk rotation speed of the dissolution medium progressively increases towards that of the paddle 10, with a commensurate decrease in fluid turbidity. The bulk movement and reduced turbidity of dissolution medium causes particles of disintegrated (but undissolved) test product to accumulate in a mound 14 at the bottom of the vessel 4. The size of the mound 14 is influenced by many factors, including the precise shape of the mixing vessel. In the case of glass mixing vessels, which are typically hand-blown, normal manufacturing variations can produces noticeable variations in the observed size of the mound 14. The presence of a mound 14 of un-dissolved product reduces interaction between the solid particles and the dissolution medium 12, which leads to artificially low dissolution rates. Since the size distribution of particles varies randomly from test to test, the actual effect in each case is a statistical quantity that is inherently non-repeatable.
The lack of turbidity and presence of a mound 14 of undissolved product are also important factors that prevent correlation between results drug dissolution tests and bio-studies of the same product. In particular, the action of the GI tract tends to produce high turbidity, but very little bulk movement, of gastric fluids. Furthermore, disintegrated solid particles do not accumulate within the GI tract, but rather are rapidly dispersed. While the dissolution medium used in dissolution tests can be (and frequently is) chemically similar to typical gastric fluids, the fluid conditions (e.g. low turbidity, high bulk movement, high particle accumulation) within the conventional dissolution test apparatus are entirely different from those of the GI tract.
Accordingly, a technique for reproducible and physiologically relevant dissolution testing of pharmaceutical products remains highly desirable.